Since the time when humans first learned to record their thoughts in written form, codes have kept sensitive information from prying eyes. But conveying information through a code requires someone who can read it as well as write it. The same is true for one of nature´s methods for transmitting information that activates or silences a gene: the "histone code."

First formally proposed in 2000 by C. David Allis, Ph.D., and his postdoctoral fellow Brian Strahl, Ph.D., the histone code is a pattern of chemical flags that decorates the "tails" of spool-like proteins called histones. Double-helical DNA, spanning some seven feet in length, wraps around histones to condense and compact itself in the nucleus of all body cells. Together, histones and DNA form a largely protective and highly constrained structure called chromatin.

In the August 1 issue of Genes & Development, Allis, along with Rockefeller University colleagues Wolfgang Fischle, Ph.D., and Yanming Wang, Ph.D., and a team of researchers at University of Virginia led by Sepideh Khorasanizadeh, Ph.D., report that protein modules called chromodomains "read" the histone code responsible for silencing, or switching off, genes.

The discovery of histone code "readers" is a crucial next step in unlocking its secrets.

"Understanding chemical modifications to histones is becoming increasingly important for understanding such diseases as cancer," says Allis, Joy and Jack Fishman Professor and head of the Laboratory of Chromatin Biology at Rockefeller. "Ultimately, determining which proteins read the histone code will enable us to develop improved treatments for cancer in humans."

In addition, many scientists, including Allis, believe these chemical modifications are responsible for passing on inherited traits without changing the sequence of DNA, an emerging field called epigenetics.

The scientists demonstrate that chromodomains guide certain proteins to specific locations on the histone tail. And what´s more, they provide evidence that chromodomains, a form of molecular Velcro, read the histone code by distinguishing between two similar locations on the histone tail, a flexible protein chain that pokes through the tightly folded chromatin complex. Each chromodomain therefore docks to a specific location, but not another.

The research reported in the Genes & Development paper focuses on a chemical reaction called methylation that occurs on histone H3 (histones are made of four subunits called H2A, H2B, H3 and H4). During methylation, an enzyme called HMT (histone methyltransferase) attaches a methyl chemical group to lysine, one of the 20 amino acid building blocks of proteins. Lysine, in fact, is methylated at two similar, but not identical, positions in the tail of histone H3: at position 9 (Lys9) and position 27 (Lys27).

"Histone methyltransferases are one of the enzyme classes in the cell nucleus that `writes´ the histone code," says Allis.

In 2001, Allis´ laboratory at the University of Virginia (he joined Rockefeller in March 2003) showed that a protein called HP1 docks to methylated Lys9. HP1 is a protein associated with heterochromatin, a condensed form of chromatin that silences genes.

Importantly, Allis´s team showed that HP1´s chromodomain was the molecular Velcro that attached to methylated Lys9. A year later Khorasanizadeh and co-workers at University of Virginia used X-ray crystallography to visualize how the HP1 chromodomain recognizes the methylation mark on Lys9.

In the Genes & Development paper, Allis and Khorasanizadeh describe how another silencing protein, called Polycomb, binds to methylated Lys27. Both the HP1 and Polycomb chromodomains, although very similar in structure and composition, differ by a few amino acids. This difference ensures that HP1 only docks to a methylated Lys9, and Polycomb only docks to methylated Lys27.

"The structure tells us that the two chromodomains literally use the amino acids that are different between them," says Allis. "Each chromodmain contains a tiny groove that extends further than the sequence that´s immediately identical, and that´s where the molecular discrimination occurs."

In a crucial experiment, Allis and colleagues swapped the chromodomain on HP1 with the chromodomain on Polycomb. When the altered proteins were added to insect cells, they switched their chromosomal targets: HP1 docked with methylated Lys27 where Polycomb normally resides, and Polycomb docked with methylated Lys9 where HP1 normally resides.

"This shows conclusively that chromodomains act as guides to take these proteins to specific methyl marks on the histone tails," says Allis.

Both HP1 and Polycomb play important roles in silencing certain genes crucial for proper development of embryos in a range of species from fruit flies to humans. Loss of HP1 correlates with metastasis in human breast cancer cells, and mutations in Polycomb proteins have been linked to cancers of the prostate and the immune system.

"Methylated Lys9 and Lys27 are two of the hottest histone modification targets in cancer research," says Allis. "Now that we know how HP1 and Polycomb bind to their respective methyl marks, the next step is try to better understand how these effectors are released at the time during the cell cycle or during development when they are no longer needed to silence genes".

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